p53 is the most commonly mutated gene in human cancer. Loss of p53-dependent apoptosis contributes to tumorigenesis, tumor progression and chemotherapeutic drug resistance. Tumor-derived mutants of p53 lose the properties of DNA binding, transactivation, apoptosis induction and suppression of cancer colony growth. The applicant has investigated the role of p53 as a determinant of chemosensitivity and identified an ovarian teratocarcinoma cell line where targeted degradation of p53 led to 100- to 1000-fold decrease in chemosensitivity in multiple clones. Using subtractive hybridization he has identified KILLER/DR5 as a DNA damage-inducible apoptosis-inducing p53-regulated death receptor gene. KILLER/DR5 expression appears to be decreased in human cancer cell lines that do not express wild-type p53. KILLER/DR5 maps to human chromosome 8p21, a location where tumor suppressors are believed to reside in several human tumor types include head and neck and prostate cancer. We plan to investigate the role of KILLER/DR5 as a tumor suppressor gene and loss of function of a head and neck tumor-derived truncating mutant that we have identified. These experiments could lead to novel strategies for anti-cancer therapy.